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Intermediate stage HCC treatment options : DEB-TACE

Intermediate stage HCC treatment options : DEB-TACE. TACE: an evolving technique toward improving the treatment of HCC. From Non-selective treatment of the entire liver parenchyma. From “Homemade” drug-in-oil emulsions and embolic agents (“conventional” TACE). To Selective treatment

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Intermediate stage HCC treatment options : DEB-TACE

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  1. Intermediate stage HCC treatment options: DEB-TACE

  2. TACE: an evolving technique toward improving the treatment of HCC From Non-selective treatment of the entire liver parenchyma From “Homemade” drug-in-oil emulsions and embolic agents (“conventional” TACE) To Selective treatment (segmental approaches with microcatheters) To Drug-eluting bead (calibrated embolic microsphere) Lencioni R. Personal communication. Hong K, et al. Clin Cancer Res. 2006;12:2563-7. www.biocompatibles.com.

  3. Advances in TACE delivery: DC Bead DC Bead Embolic microsphere developed for TACE Actively sequesters doxorubicin hydrochloride from solution and releases it in a controlled and sustained fashion www.biocompatibles.com

  4. SO3 Dex SO3 SO3 Dex SO3 SO3 SO3 Dex SO3 Dex SO3 SO3 SO3 SO3 Dex SO3 Dex Dex SO3 SO3 SO3 SO3 Dex SO3 SO3 SO3 SO3 Dex Dex Dex SO3 SO3 SO3 SO3 SO3 SO3 Dex Dex Mechanism of Loading the Drug Eluting Beads with Doxorubicin The doxorubicin is loaded and eluted by “reversible ionic exchange mechanism” Hydrated Beads Loaded Beads Hydration shell associated with PVA and ionic groups Bulk (non-bound) water Interaction of doxorubicin with SO3 groups displaces water from the hydration shells www.biocompatibles.com

  5. Chemotherapy TACE Drug-elutingBead Drug Eluting Bead Drug Distribution Schematic showing the relative drug distribution for standard arterial chemotherapy vs conventional TACE vs PRECISION TACE with DEB DoxorubicinArterialInjection 1. Doxorubicin+ Iodised Oil 2. Embolization DoxorubicinDrug-elutingBead DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  6. DEB-TACE vs. conventional TACE: Pharmacokinetics DEB-TACE Conventional TACE 1000 1000 800 800 600 600 Doxorubicin at serum (ng/mL) Doxorubicin at serum (ng/mL) 400 400 200 200 0 0 6 h 7 d 2 h 2 h 6 h 7 d 24 h 48 h 24 h 48 h 5 min 5 min 20 min 40 min 60 min 20 min 40 min 60 min Baseline Baseline • Serum doxorubicin levels at different time points in patients receiving TACE with DC-bead (n=13) or conventional TACE (n=5)1 DC, doxorubicin-capable (doxorubicin loaded); DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Varela M, et al. J Hepatol 2007;46:47481.

  7. Chemoembolization of HCC with Drug-Eluting Beads DEB-TACE Varela M et al. J Hepatol. 2007; 46(3): 474-81

  8. PRECISION TACE Conventional TACE Systemic Exposure (Cmax) PRECISION TACE with DEB vs Conventional TACE 2000 1500 CMAX ng/mL 1000 500 0 Varela et al [150 mg]Poon et al Varela et al Raoul et al 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  9. PRECISION TACE Conventional TACE Systemic Exposure (AUC) PRECISION TACE with DEB vs Conventional TACE 2000 1500 AUC (ng/mixmin) 1000 500 0 Varela et al Varela et al 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  10. Trial Design • Randomized phase II study to assess the safety and efficacy of chemoembolization with DEB and doxorubicin (PRECISION TACE with DEB) in an international, multi-center trial • Primary endpoints: 6 month tumor RR Measured by MRI, response criteria EASL (necrosis) • Secondary endpoints: safety, response (RECIST), local tumor response (EASL), AFP, time to discharge, cardiotoxicity, QoL DEB RANDOMIZATION • Eligible Patients • HCC not suitable for curative treatments • Patients with multinodular HCC without • Vascular invasion • Extrahepatic spread • Recurrence following resection or percutaneous ablation • Performance status ECOG 0 and 1 • Patients with preserved liver function (Child Pugh A and B) • Patients on the transplant list who may not receive a transplant within 6 months n=100 cTACE n=100 DEB=drug eluting beads (chemoembolization with DEB and doxorubicin); cTACE=conventional transarterial chemoembolization. 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  11. Exclusion Criteria (Main) • Exclusion Criteria • Patients with another primary tumor • Patients previously with chemo- or radiotherapy • Advanced liver disease • Bilirubin levels >3 mg/dL • Advanced tumorial disease • Vascular invasion or extrahepatic spread • Diffuse HCC defined as >50% tumor involvement of the whole liver • Any contraindication for doxorubicin administration • Any contraindication for hepatic embolization procedures 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  12. Protocol Design and Treatment Schedule Patient Population Visit 1Baseline Assessment/Randomization Visit 21st Chemoembolization Treatment Visit 31 Month MRI Visit 42nd Chemoembolization Treatment Visit 53 Month MRI Visit 63rd Chemoembolization Treatment Visit 76 Month MRI & Study Completion 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  13. 212 Patients Enrolled Vienna Athens Mainz Lille Frankfurt Lyon Zurich Geneva Paris – Villejuif (HPB) Paris – HPS Nice Hannover Paris – Villejuif (GR) Lausanne Paris – Clichy Damstadt 0 5 10 15 20 25 30 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  14. Patient Demographics * BCLC Classification according to tumor stage (Llovet et al Lancet 2003). 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  15. Baseline Stratification: Four Prognostic Factors 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  16. Analyzed Population 212 PatientsRandomized DEBn=102 cTACEn=108 9 2 T1n=93 T1n=108 Analyzed Population 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  17. Product, Dose and Technique Guidelines • Precision TACE with DEB • 2 x 2 mL vials of DEB (total 4 mL) loaded at 37.5 mg/mL for total doxorubicin dose of 150 mg • 1 vial of 300-500 μm followed by 1 vial of 500-700 μm • cTACE • Doxorubicin dose of 50-75 mg/m2 to maximum of 150 mg • Physician preference for embolic • Technique for both groups • Unifocal tumors treated with selective segmental chemoembolization • Microcatheter could be used • Bilobar disease: both lobes treated within a 3-week period • Embolization to stasis in 2nd or 3rd order branches • DEB group: additional bland embolic could be used 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  18. Number of Treatments Percentage of Patients in the Analyzed Population Who Received 1, 2 or 3 Chemoembolization Treatments DEB 100 100 100 cTACE 80 82.8 81.5 Technical success DEB 97% cTACE 99% 60 61.3 56.5 40 20 0 1 2 3 No of Treatments Note: 8 DEB patients, and 5 cTACE patients received 2 sessions at T1 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  19. Doxorubicin Dose Per Treatment 160 140 120 100 80 DEB cTACE 60 40 20 0 Treatment 1 Treatment 2 Treatment 3 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  20. DEB-TACE vs. conventional TACE: Tumour response 70 60 50 56(52%)47(44%) 24(22%) DEB-TACE 59(63%) 48(52%) 25(27%) 40 DCR OR Response (%) 30 CR cTACE 20 DCR OR 10 CR 0 cTACE DEB-TACE PRECISION V trial cTACE, conventional TACE.1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  21. DEB cTACE Disease Control Objective Response Complete Response 6-Month Response in Less Advanced Patients Response (%) 70 67 61 60 63 61 58 56 50 50 54 54 52 48 51 46 48 45 40 46 30 35 27 28 27 25 25 21 20 21 10 0 Child Pugh B ECOG 1 Unilobar Not Recurrent 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  22. DEB cTACE Disease Control Objective Response Complete Response 6-Month Response in More Advanced Patients DEB demonstrated statistically significantadvantage in advanced patientsObjective Response (P=.038) and Disease Control (P=.026) P≤.05 70 73 60 63 63 59 55 54 50 49 49 Response (%) 40 44 40 37 30 32 31 32 29 27 25 20 21 17 15 13 14 16 10 0 RecurrentDisease Child Pugh B ECOG 1 Bilobar 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  23. DEB-TACE: Overall and progression-free survival in a Phase II trial 100 Overall survival (median=26 mo.) 80 Progression-free survival (median=20 mo.) 60 Survival probability (%) 40 • N=20 (total) • Embolization repeated up to twice if <90% necrosis on MRI 20 0 0 10 20 30 40 Time (months) DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Reyes DK, et al. Cancer J 2009; 15:526532.

  24. DEB-TACE vs. bland embolization: Recurrence rates 1.0 Patients embolized at set time intervals (2 months), with a maximum of 3 embolizations 0.8 DEB-TACE (n=41) P < 0.0001 Bland embolization (n=43) 0.6 Recurrence rate 0.4 0.2 0 1 3 6 9 12 Time (months) DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Malagari K et al. Cardiovasc Intervent Radiol 2010; 33:541-51.

  25. Incidence of New Lesions at 6 Months • The probability of new lesions forming was the same in both study arms 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  26. Time-to-Progression: All Lesions 1.0 × DEB: Median 217 days ± 7.84 × × × CEL: Median 196 days ± 14.92 × × × × 0.8 × × × × × 0.6 × Probability of No Progression × × × × 0.4 × × 0.2 0 0 50 100 150 200 250 300 350 Days 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  27. Safety-Related Events per 100 Treatments Related* Grade 3 and 4 AEs Related* AEs 100 20 80 15 17 79 60 13 10 58 40 5 20 0 0 DEB cTACE DEB cTACE * Related is investigator-assessed “definitely or probably related to treatment” 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  28. 0 Doxorubicin-Related Side Effects 40 DEB cTACE 35 Alopecia Mucosis 30 Marrow Suppression P=.0001 Skin Discoloration 25 20 Events per 100 Patients 15 10 5 DEB cTACE Adapted from Lencioni R et al. Poster Presented at ASCO Annual Meeting; May 29-June 2, 2009; Orlando, FL.

  29. Safety-Serious Adverse Events (SAEs) SAEs Related* SAEs 25 8 7 20 7 22 22 6 6 5 15 4 Events per 100 Treatments 10 3 2 5 1 0 0 DEB cTACE DEB cTACE * Related is investigator-assessed “definitely or probably related to treatment” 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  30. Gastrointestinal and Liver Serious Adverse Events (SAEs) Liver Toxicity Pancreatic &Gallbladder Pathology GI Bleeding Abscess and infection GI Ulcer Ascites Hospitalization for TIPS Intratumoral Bleeding DEB Other cTACE 0 2 4 6 8 10 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  31. Serious Adverse Events Advanced Disease DEB cTACE 40 30 32 32 31 31 27 26 24 20 SAE Event Rates* 19 10 0 Child Pugh B ECOG 1 Bilobar Disease Recurrent Disease • Per 100 patients, events within 30 days of treatment. 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  32. Liver Toxicity: AST & ALT Levels DEB cTace AST 250 200 150 P=.001 AST Units/L 100 50 0 Timepoint 1 2 3 4 5 6 7 8 9 ALT 200 150 ALT Units/L P=.001 100 50 0 Timepoint 1 2 3 4 5 6 7 8 9 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  33. Deaths Deaths Due to Disease Progression 3 2 1 0 DEB cTACE 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  34. DEB-TACE vs. conventional TACE: Tolerability PRECISION V trial DEB-TACE associated with improved tolerability vs conventional TACE:1 • Significant reduction in serious liver toxicity (p < 0.001) • Significantly lower rates of doxorubicin-related side effects (p = 0.0001) DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Lammer J, et al. Cardiovasc Intervent Radiol 2010;33:4152.

  35. Summary • Overall, compared to cTACE, DEB has • Greater objective response (P=.11) • Lower related SAEs and AEs • Compared to cTACE, DEB has a significant (P<.05) advantage in • Objective response in more advanced patients (P=.038) • Disease control in more advanced patients (P=.026) • Compared to cTACE, DEB has a highly significant • advantage in the (P<.01) • Reduction of doxorubicin associated side effects in all patients (P=.0001) • Reduction of liver toxicity in all patients (AST: P=.001; ALT P=.0001) 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  36. Conclusion • PRECISION TACE with DEB is safe, efficacious and reproducible • There is a significant advantage of PRECISION TACE with DEB in more advanced patients – those with more compromised liver function, poorer performance status, bilobar disease and recurrent disease – greater response, greater disease control and improved safety • Currently AASLD guidelines do not recommend chemoemboliztion for Child B and ECOG 1 patients. The PRECISION V data show that these patients can now be safely treated with PRECISION TACE with DEB Combination of PRECISION TACE with DEB and Sorafenib is currently being investigated with the aim of further improving the long-term outcomes of intermediate-stage HCC patients 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  37. DEB-TACE: Summary DEB-TACE is a valuable alternative to conventional TACE, providing: Improved pharmacokinetics with reduced systemic exposure to doxorubicin1 Reduced liver toxicity2,3 Fewer doxorubicin-related side effects2 Improved response rates in patients with negative prognostic factors, including:2 Child-Pugh B status ECOG PS 1 Bilobar disease Recurrent disease DEB, drug-eluting beads; ECOG PS, Eastern Cooperative Oncology Group performance status; TACE, transarterial chemoembolization.1. Varela M, et al. J Hepatol 2007;46:474-481;2. Lencioni R, et al. ASCO 2009, abstr 4523; 3. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

  38. DEB-TACE vs. conventional TACE: Liver toxicity (ALT-AST levels) 250 p=0.001 200 150 100 50 0 200 p<0.001 150 100 50 0 PRECISION V trial AST (units/L) DEB-TACE ConventionalTACE Mean ratio pre-discharge/pre-TACE ALT (units/L) 1st 2nd 3rd Chemoembolization procedure DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Lencioni R, et al. ASCO 2009; abstr. 4523. Poster discussion available at: www.asco.org; 2. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

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